NM_000215.4(JAK3):c.2350G>A is a variant predicted to cause the substitution of aspartic acid with asparagine at amino acid 784 (p.Asp784Asn); however, functional studies demonstrate this variant instead acts as a splice-altering variant. c.2350G>A sits at the last nucleotide of exon 17 and was functionally confirmed to disrupt splicing, resulting in skipping of exon 17, as demonstrated by RT-PCR and Sanger sequencing of the resulting cDNA. Exon 17 lies within the functionally important JH1 catalytic kinase domain. Additionally, the out-of-frame deletion of exon 17 introduces a frameshift (p.Asp784Asnfs*60) predicted to undergo NMD (PVS1; PMID: 30177960). The grpmax filtering allele frequency of this variant is 0.00001747 in gnomAD v4.1.1, which is below the ClinGen SCID VCEP threshold (<0.000115) for PM2_Supporting, and no homozygotes have been observed. This variant therefore meets PM2_Supporting. This variant was found in the homozygous state in 2 SCID patients from 2 unrelated families (PMID: 30177960): one born to consanguineous parents (first-degree cousins, 0.5 point) and one born to non-consanguineous parents (1.0 point). A total of 1.5 points meets the PM3 threshold. At least one SCID patient (PMID: 30177960) underwent SCID panel/whole-exome sequencing, which identified this JAK3 variant in the homozygous state with no alternative explanation (1.0 point). The patient had a family history of SCID, with a sibling who died at 6 months of age with a SCID-like presentation (0.5 point). The patient met SCID diagnostic criteria, with persistently low autologous T cell counts documented from 2 months of age (0.5 point). The patient also presented with a T-B+NK- lymphocyte subset profile confirmed by flow cytometry (0.5 point). A total of 2.5 points were assigned, meeting the PP4_Moderate criterion. In summary, this variant meets the criteria for classification as Pathogenic for autosomal recessive severe combined immunodeficiency due to JAK3 deficiency, based on the ACMG/AMP criteria as specified by the ClinGen SCID VCEP: PVS1, PM3, PP4_Moderate, PM2_Supporting (VCEP specifications version 2.3.0).